- NOVEL SUBSTITUTED PYRIDO-PIPERAZINONE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted pyrido-piperazinone derivatives of Formula (I) wherein R1, R2, R3, R4, R5, L, Z and X have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Paragraph 0567-0568
(2018/11/26)
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- Structure-based drug design of novel potent and selective tetrahydropyrazolo[1,5-a]pyrazines as ATR inhibitors
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A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series. (Chemical Equation Presented).
- Barsanti, Paul A.,Aversa, Robert J.,Jin, Xianming,Pan, Yue,Lu, Yipin,Elling, Robert,Jain, Rama,Knapp, Mark,Lan, Jiong,Lin, Xiaodong,Rudewicz, Patrick,Sim, Janet,Taricani, Lorena,Thomas, George,Xiao, Linda,Yue, Qin
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supporting information
p. 37 - 41
(2015/01/30)
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- Discovery of novel 2-(alkylmorpholin-4-yl)-6-(3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones as orally-active GSK-3β inhibitors for Alzheimer's disease
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We herein describe the results of further evolution of GSK-3β inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3β inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models.
- Fukunaga, Kenji,Sakai, Daiki,Watanabe, Kazutoshi,Nakayama, Kazuki,Kohara, Toshiyuki,Tanaka, Hiroshi,Sunada, Shinji,Nabeno, Mika,Okamoto, Masako,Saito, Ken-Ichi,Eguchi, Jun-Ichi,Mori, Akiko,Tanaka, Shinji,Inazawa, Keiko,Horikawa, Takashi
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p. 1086 - 1091
(2015/02/19)
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- NOVEL SUBSTITUTED PYRIDO-PIPERAZINONE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted pyrido-piperazinone derivatives of Formula (I) wherein R1, R2, R3, R4, R5, L, Z and X have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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- NOVEL HEPATITIS C VIRUS INHIBITORS
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The invention provides compounds of formula (I): wherein Rings A and A' are independently 5-membered optionally substituted aromatic heterocycles; Q is C(=O)NR1R1' or formula U is C(R4)2, O, S, S(=O)2, C(R4)2C(R4)2, CH2O, OCH2, CH2S, SCH2, CH2S(=O)2, S(=O)CH2 or C=C(Ru )2; X is CH2, CHR12, CR12R12, O, S, S(=O)2 or NRx; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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- SUBSTITUTED 3, 4 - DIHYDRO - 2H - PYRIDO [1, 2 -A] PYRAZINE - 1, 6 - DIONE DERIVATIVES USEFUL FOR THE TREATMENT OF (INTER ALIA) ALZHEIMER'S DISEASE
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The present invention is concerned with novel substituted 3,4-dihydro-2H-pyrido[1,2- a]pyrazine-1,6-dione derivatives of Formula (I) wherein R1, R2, R3, R4, R5, Z and X have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 79
(2013/12/03)
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- A facile synthetic route to diazepinone derivatives via ring closing metathesis and its application for human cytidine deaminase inhibitors
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A variety of diazepinone derivatives were prepared from α-amino acids and amino alcohols by a new synthetic methodology based on ring closing metathesis as a key step. The diazepinones were coupled with ribose derivatives to afford novel diazepinone nucleosides. Among them, (4R)-1-ribosyl-4-methyl-3, 4-dihydro-1H-1,3-diazepin-2(7H)-one (3) showed a potent inhibitory effect (Ki = 145.97 ± 4.87 nM) against human cytidine deaminase.
- Kim, Minkyoung,Gajulapati, Kondaji,Kim, Chorong,Jung, Hwa Young,Goo, Jail,Lee, Kyeong,Kaur, Navneet,Kang, Hyo Jin,Chung, Sang J.,Choi, Yongseok
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supporting information
p. 11443 - 11445
(2013/01/15)
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- Synthesis of the azetidinyl-thiazoline fragment of vioprolides A and C
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An efficient synthesis of the azetidinyl-thiazoline fragment of the antifungal and cytotoxic macrolides vioprolides A and C is reported. Key steps of the synthesis include formation of the thiazoline by condensation of NAlloc-trans (2S,4R)-4-methylazetidine-2-carbonitrile with L-cysteine and formation of the four-membered ring by intramolecular alkylation of a suitably protected N-Alloc derivative prepared from (R)-alaninol.
- Chopin, Nathalie,Couty, Francois,Evano, Gwilherm
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p. 353 - 359
(2011/04/12)
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- 2-(CYCLIC AMINO)-PYRIMIDONE DERIVATIVES AS TPK1 INHIBITORS
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A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof (I) wherein R2 represents a hydrogen or the like; R3 represents methyl group or the like; R20 represents a halogen atom or the like; q represents an integer of 0 to 3; Z represent nitrogen atom, CH, or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents a substituted alkyloxy and the like; p represents an integer of 0 to 3; X represents bond, CH2, oxygen atom, NH, or the like; any one or more of R5 and R6, R5 and R4, R6 and R4, X and R5, X and R4, X and R6, and R6 and R6 may combine to each other to form a ring, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).
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Page/Page column 197; 215-216
(2008/06/13)
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- Identification of a broad-spectrum azasordarin with improved pharmacokinetic properties
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The synthesis and antifungal activity of 5′- and 5′-6′-substituted azasordarin derivatives are described. Modification of the 5′-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5′-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
- Serrano-Wu, Michael H.,St. Laurent, Denis R.,Carroll, Tina M.,Dodier, Marco,Gao, Qi,Gill, Patrice,Quesnelle, Claude,Marinier, Anne,Mazzucco, Charles E.,Regueiro-Ren, Alicia,Stickle, Terry M.,Wu, Dedong,Yang, Hyekyung,Yang, Zheng,Zheng, Ming,Zoeckler, Mary E.,Vyas, Dolatrai M.,Balasubramanian, Balu N.
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p. 1419 - 1423
(2007/10/03)
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- 3-(Imidazolyl)-2-alkoxypropanoic acids
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Compounds according to formula (I) wherein n is 0-3, R1 is optionally substituted C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, Heterocycle, Aromatic heterocycle, Aryl or hydrogen and R2, R3, R4, R5, R6, R7, R8 and R9 are each independently selected from hydrogen and optionally substituted C1-6 alkyl, or R5 and R8 are an alkylene chain, are novel. They are useful in the treatment of thrombotic conditions and other pathologies associated with fibrin deposition.
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